Acute kidney injury (AKI) is a severe disease characterized by a rapid loss in renal function leading to substantial morbidity and mortality. Frequent causes of AKI include ischemia/reperfusion (I/R) injury and acute drug or toxicant exposure. Despite attempts to develop new therapeutic strategies to treat AKI, few have been successful, and mortality has remained unchanged for several decades. Therefore, novel pathways and novel targets must be examined for the development of beneficial therapies for AKI. It has been shown that renal proximal tubule cells (RPTC) exhibit severe mitochondrial dysfunction following toxicant exposure or I/R injury. Mitochondrial dysfunction exacerbates cell injury, impairs energy-dependent repair, and leads to end organ kidney damage and failure in a variety of tissues. Our laboratory has demonstrated persistent mitochondrial dysfunction and depletion of mitochondrial proteins following renal I/R injury that correlates with sustained renal dysfunction in mice. We have also demonstrated that injured renal proximal tubules can recover if they are induced to generate new mitochondria through mitochondrial biogenesis (MB). Peroxisome proliferator-activated receptor gamma coactivator-1? (PGC-1?) is thought to be the master regulator of MB, and is enriched in tissues with high metabolic demand, such as the kidney. Recently, we determined that during I/R-induced AKI the mitogen-activated protein kinase (MAPK) extracellular signal-related kinase 1/2 (ERK1/2) is activated (phosphorylated) early and sustained over time. ERK1/2 has been shown to become phosphorylated due to ischemia in various tissues with ROS being a main instigator of activation. We have shown in RPTC that inhibition of ERK1/2, with the MEK1/2 inhibitor trametinib, PGC- 1? mRNA is increased under control conditions, in addition to showing trametinib inhibits ERK1/2 in mouse renal cortex after intraperitoneal injections. The role of ERK1/2 in PGC-1? and mitochondrial function has received little attention, despite being the most studied MAPK. We hypothesize that ERK1/2 regulates renal PGC-1?, MB, and mitochondrial homeostasis under control conditions and that ERK1/2 activation following renal I/R suppresses PGC-1? transcription and MB, and contributes to both mitochondrial and renal dysfunction. This hypothesis will be addressed through the following Specific Aims. Aim 1 will address the role of ERK1/2 signaling on PGC-1?, MB and mitochondrial homeostasis under control conditions and following oxidant injury in primary cultures of RPTC. Pharmacologic inhibitors and siRNA technology will confirm the relevant signaling pathways for ERK1/2 activation and ERK1/2 actions on PGC-1?, MB and mitochondrial homeostasis. Aim 2 will elucidate the role of ERK1/2 signaling in PGC-1?, MB and mitochondrial homeostasis in the renal cortex of nave mice. Aim 3 will investigate the role of ERK1/2 signaling on mitochondrial and renal dysfunction in I/R- induced AKI in mice.